Bicyclic guanidine derivatives and therapeutic uses thereof

ABSTRACT

The invention relates to compounds of general formula (I), in which A, X, Y and R1 are defined in Claim  1 . These compounds may be used in the treatment of pathologies associated with insulin resistane syndrome.

The present invention relates to bicyclic guanidine derivatives that areuseful in the treatment of pathologies associated with insulinresistance syndrome.

Bicyclic guanidine derivatives with antihypertensive or antimicrobialproperties have been described in U.S. Pat. Nos. 3,855,242, 4,260,628and Yaoxue Xuebao, 1982, 17(3), 229-232.

The present invention is directed towards providing novel bicyclicguanidine compounds with novel properties.

The present invention therefore relates to a compound of the generalformula (I)

in which

-   A represents a benzene or pyridine ring which is optionally    substituted by one or more of the following groups:    -   branched or unbranched (C₁-C₂₀)alkyl,    -   OR2, where R2 represents:        -   H,        -   branched or unbranched (C₁-C₅)alkyl,        -   (C₃-C₈)cycloalkyl, or        -   benzyl,    -   NR3R4, where R3 and R4 represent, independently of each other:        -   H,        -   branched or unbranched (C₁-C₂₀)alkyl,        -   benzyl,        -   acetyl,        -   (C₃-C₈)cycloalkyl,        -   or alternatively R3 and R4 together form a 3- to 8-membered            ring including a nitrogen atom,    -   SR5, where R5 represents:        -   H,        -   branched or unbranched (C₁-C₅)alkyl,        -   (C₃-C₈)cycloalkyl, or        -   benzyl,    -   halogen    -   cyano    -   nitro    -   CO₂R6, where R6 represents:        -   H or        -   branched or unbranched (C₁-C₅)alkyl, or    -   trifluoromethyl,-   X represents a —CH═, —CH₂—, —N═ or —NH— radical,-   Y represents a CH₂ radical, an oxygen or sulfur atom or a group    —NR7, where R7 represents:    -   H,    -   branched or unbranched (C₁-C₅)alkyl,    -   benzyl,    -   (C₃-C₈)cycloalkyl, or    -   a CH₂CO₂H group,-   R1 represents one of the following groups    -   H,    -   branched or unbranched (C₁-C₅)alkyl, or    -   benzyl        with the exception of the compounds of the formula (I) in which:-   a—A represents a benzene ring, X represents —CH═ or —CH₂—, Y    represents an oxygen atom and R1 is a hydrogen atom;-   b—A represents a benzene ring substituted in position 5′ of the    double ring with a halogen atom, X represents —CH═, Y represents a    sulfur atom and R1 is a hydrogen atom,-   c—A represents an unsubstituted benzene ring, X represents —CH₂—, R1    is a hydrogen atom or a branched or unbranched (C₁-C₅)alkyl radical    and Y represents NR7, where R7 represents a hydrogen atom, a    branched or unbranched (C₁-C₅)alkyl radical or a benzyl radical,-   d—A represents an unsubstituted benzene ring, X represents —CH═, R1    is a hydrogen atom and Y represents NR7, where R7 represents an    ethyl radical, and also the tautomeric, enantiomeric,    diastereoisomeric and epimeric forms, the solvates and the    pharmaceutically acceptable salts.

Among the branched or unbranched C₁-C₂₀ alkyl radicals that mayespecially be mentioned are the methyl, ethyl, propyl, isopropyl, butyl,sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl,dodecyl, pentadecyl and hexadecyl radicals.

One particular group of compounds of the formula (I) is that in whichthe alkyl radicals are C₁-C₅ alkyl radicals.

Among the C₃-C₈ cycloalkyl radicals that may especially be mentioned arecyclopropyl, cyclopentyl, cyclohexyl and cycloheptyl radicals.

3- to 8-membered rings including a nitrogen atom that may especially bementioned are aziridine, pyrrolyl, imidazolyl, pyrazolyl, indolyl,indolinyl, pyrrolidinyl, piperazinyl and piperidyl rings.

Another particular group of compounds of the formula (I) is that inwhich A represents an optionally substituted benzene ring. Oneparticular sub-group is the one in which X represents a —CH═ radical ora —CH₂— radical. Another particular sub-group is the one in which Xrepresents an —N═ radical or an —NH— radical.

Another particular group of compounds of the formula (I) is the one inwhich Y represents a —CH₂— radical, a sulfur atom or a group —NR7, whereX preferably represents —CH═ or —CH₂.

One sub-group targets these compounds of the formula (I) in which Arepresents a substituted benzene ring, more preferably a benzene ringmono-substituted in a position other than position 5′ of the doublering, or a benzene ring substituted by at least two groups.

One particular sub-group of compounds of the formula (I) is the one inwhich Y is a sulfur atom and A represents a benzene ring monosubstitutedin a position other than position 5′ of the double ring, or a benzenering substituted by at least two groups.

Another particular sub-group of compounds of the formula (I) is the onein which Y is a group —NR7 and A represents a substituted benzene ring.

Another particular group of compounds of the formula (I) is the one inwhich Y represents a —CH₂— radical, a sulfur atom or a group —NR7, whereA preferably represents a substituted benzene ring, more preferably abenzene ring monosubstituted in a position other than position 5′ of thedouble ring, or a benzene ring substituted by at least two groups.

The invention also relates to the tautomeric, enantiomeric,diastereo-isomeric and epimeric forms of the compounds of the generalformula (I).

The compounds of the general formula (I) contain basic nitrogen atomsthat may be monosalified or disalified with organic or mineral acids.

The compounds of the general formula (I) may be prepared from a compoundof the general formula (II):

in which A, X, Y and R1 have the definitions specified above, andaccording to the methods for obtaining a guanidine that are described inthe literature.

By way of example, these methods are especially described in thefollowing literature: Tetrahedron Letters, 1993, 34(48), 7677-7680;Tetrahedron Letters, 1993, 34(21), 3389-3392; Tetrahedron Letters, 1996,37(14), 2483-2486; WO 98/52917; Journal of Medicinal Chemistry, 1990,33(1), 434-444; Journal of Organic Chemistry, 1998, 63, 3804-3805; WO94/29269; Tetrahedron Letters, 1994, 35(7), 977-980; Journal of OrganicChemistry, 1992, 57, 2497-2502; Synthesis, 1986, 777-779; SyntheticCommunications, 1987, 17(15), 1861-1864.

The compounds of the formula (II) are prepared by simple and standardreactions readily available to those skilled in the art. By way ofexample, the following references illustrate these syntheses: OppiBriefs, 1996, 28(6), 702-704; Heterocycles, 1988, 27(6), 1421-1429;Pharmazie, 1999, 54(9), 651-654; WO 95/09159; WO 91/09023; WO 97/42183;Synthetic Communications, 1993, 23(6), 743-748; Journal of the AmericanChemical Society, 1952, 74, 664-665; DE 2 739 723; Journal of MedicinalChemistry, 1994, 37(23), 3956-3968; WO 93/17025; WO 96/00730;Heterocycles, 1995, 41(3), 477-486; Journal of Medicinal Chemistry,1968, 11, 1164-1167; Monatshefte für Chemie, 1957, 1087-1094; Journal ofMedicinal Chemistry, 1989, 32, 1988-1996.

The compounds according to the present invention, and more generally thecompounds of the formula (I)

in which:

-   A represents a benzene or pyridine ring optionally substituted by    one or more of the following groups:    -   branched or unbranched (C₁-C₂₀)alkyl,    -   OR2, where R2 represents:        -   H,        -   branched or unbranched (C₁-C₅)alkyl,        -   (C₃-C₈)cycloalkyl, or        -   benzyl,    -   NR3R4, where R3 and R4 represent, independently of each other:        -   H,        -   branched or unbranched (C₁-C₂₀)alkyl,        -   benzyl,        -   acetyl,        -   (C₃-C₈)cycloalkyl,        -   or alternatively R3 and R4 together form a 3- to 8-membered            ring including a nitrogen atom,    -   SR5, where R5 represents:        -   H,        -   branched or unbranched (C₁-C₅)alkyl,        -   (C₃-C₈)cycloalkyl, or        -   benzyl,    -   halogen    -   cyano    -   nitro    -   CO₂R6, where R6 represents:        -   H or        -   branched or unbranched (C₁-C₅)alkyl, or    -   trifluoromethyl,-   X represents a —CH═, —CH₂—, —N═ or —NH— radical,-   Y represents a CH₂ radical, an oxygen or sulfur atom or a group    —NR7, where R7 represents:    -   H,    -   branched or unbranched (C₁-C₅)alkyl,    -   benzyl,    -   (C₃-C₈)cycloalkyl, or    -   a CH₂CO₂H group,-   R1 represents one of the following groups    -   H,    -   branched or unbranched (C₁-C₅)alkyl, or    -   benzyl,        and also the tautomeric, enantiomeric, diastereoisomeric and        epimeric forms thereof, the solvates and the pharmaceutically        acceptable salts thereof, are useful in the treatment of        pathologies associated with insulin resistance syndrome        (syndrome X).

Insulin resistance is characterised by a reduction in the action ofinsulin (cf. Presse Médicale, 1997, 26(No. 14), 671-677) and is involvedin a large number of pathological conditions, such as diabetes and moreparticularly non-insulin-dependent diabetes (type II diabetes or NIDDM),dyslipidaemia, obesity and also certain microvascular and macrovascularcomplications, for instance atherosclerosis, retinopathies andneuropathies.

In this respect, reference will be made, for example, to Diabetes, Vol.37, 1988, 1595-1607; Journal of Diabetes and its Complications, 1998,12, 110-119 or Horm. Res., 1992, 38, 28-32.

The compounds of the invention especially have strong hypoglycaemiantactivity.

The present invention thus also relates to pharmaceutical compositionscomprising, as active principle, a compound according to the invention.

The pharmaceutical compounds according to the invention may be presentedin various forms intended for parenteral, oral, rectal, permucous orpercutaneous administration.

They will therefore be presented in the form of injectable solutions orsuspensions or multi-dose bottles, in the form of plain or coatedtablets, sugar-coated tablets, wafer capsules, gel capsules, pills,cachets, powders, suppositories or rectal capsules, solutions orsuspensions, for percutaneous use in a polar solvent, or for permucoususe.

The excipients that are suitable for such administrations are cellulosederivatives, microcrystalline cellulose derivatives, alkaline-earthmetal carbonates, magnesium phosphate, starches, modified starches andlactose for the solid forms.

For rectal use, cocoa butter or polyethylene glycol stearates are thepreferred excipients.

For parenteral use, water, aqueous solutions, physiological saline andisotonic solutions are the vehicles that are the most suitable for use.

The dosage may vary within a wide range (0.5 mg or less, to 1000 mg)depending on the therapeutic indication and the route of administration,and also the age and weight of the individual.

The examples that follow illustrate the preparation of compounds of theformula (I).

EXAMPLE 1 Synthesis of2-(aminoiminomethyl(methylamino)methyl)-benzothiazole hydrochloride

Step 1: 2-chloromethylbenzothiazole (A)

Chloroacetyl chloride (81.6 ml) is added dropwise to a solution composedof 2-aminothiophenol (112 ml, 1.04 mol), dichloromethane (1.2 l) andthree drops of dimethylformamide, while the temperature is kept below40° C. After stirring for 18 hours, the precipitate formed is filteredoff by suction and then dissolved in a minimum amount of water. Thisaqueous phase is extracted with pentane and the extracts areconcentrated under vacuum at room temperature, giving 120 g (65%) of aflaky solid.

¹H NMR (DMSO-d₆, 200 MHz): δ: 8.32, d, 1H, aromatic H; 8.21, d, 1H,aromatic H; 7.77-7.63, m, 2H, aromatic H, 5.43, s, 2H, CH₂Cl

Step 2: 2-methylaminomethylbenzothiazole (B)

A (115 g, 0.62 mol) and 580 ml of an aqueous 40% methylamine solutionare heated at 60° C. in an autoclave for 18 hours. The reaction mediumis concentrated and the residue is purified on a column of silica (7/3petroleum ether/dichloromethane) to give 96 g (87%) of anorange-coloured oil.

¹H NMR (DMSO-d₆, 200 MHz): δ: 8.03-7.39, m, 4H, aromatic H; 4.24, s, 1H,CH₂; 2.61, s, 3H, CH₃

Step 3: 2-(aminoiminomethyl(methylamino)methyl)benzothiazolehydrochloride

55.7 g (0.449 mol) of aminoiminomethylsulfonic acid are addedportionwise to a solution composed of dimethylformamide (400 ml) and B(80 g, 0.449 mol) cooled to 5° C., while the temperature is kept below5° C. After stirring for 48 hours, the reaction medium is cooled to 5°C. and 75 ml (0.9 mol) of concentrated hydrochloric acid are added.After stirring for 1 hour, the solution is concentrated and theremaining oil is taken up in acetonitrile. The precipitate formed isfiltered off by suction and then recrystallised from water to give 40 g(35%) of a white solid.

m.p.=203-205° C. ¹H NMR (DMSO-d₆, 200 MHz): δ: 8.32, d, 1H, aromatic H;8.25-7.40, m, 8H, aromatic H, NH and HCl; 5.20, s, 2H, CH₂; 3.10, s, 3H,NCH₃

¹³C NMR (DMSO-d₆, 50 MHz): δ: 168.32, 159.08, 154.12, 136.33, quaternaryC; 128.20, 127.27, 124.30 and 124.15, aromatic CH; 53.19, CH₂; 38.88,NCH₃

EXAMPLE 2 Synthesis of 2-(aminoiminomethylamino)methylbenzimidazolehydrochloride

Step 1: 2-aminomethylbenzimidazole (C)

A solution of 2-aminoaniline (27 g, 0.25 mol), glycine (27.7 g, 0.37mol) and 250 ml of 5.5M hydrochloric acid is refluxed for 30 hours andthen stored in a refrigerator for 24 hours. The precipitate formed isfiltered off with suction and then taken up in 400 ml of methanol andtreated with carbon black. The mixture is filtered and the solvent isremoved to give 22 g (49%) of a white solid.

m.p.=81-83° C.

¹H NMR (DMSO-D₆, 200 MHz): δ: 7.40-6.90, m, 4H, aromatic H; 3.70, s, 2H,CH₂

Step 2: 2-(aminoiminomethylamino)methylbenzimidazole hydrochloride

A solution of C (15 g, 0.101 mol), 1-(aminoiminomethyl)pyrazolehydrochloride (15 g, 0.102 mol) and 50 ml of dioxane is refluxed for 18hours and then concentrated to dryness. The crude product is taken up inmethanol (300 ml) and treated with carbon black. After filtration andconcentration, the residue is taken up in a minimum amount of water andthe remaining insoluble material is removed by filtration. The solutionis then freeze-dried to give 14 g (62%) of a white solid.

m.p.=171-173° C.

¹H NMR (DMSO-d₆, 200 MHz): δ: 8.20-7.10, m, 8H, aromatic H, NH and HCl;4.60, s, 2H, CH₂

¹³C NMR (DMSO-d₆, 50 MHz): δ: 158.56, 151.26, 138.98, quaternary C;122.88, 115.76, aromatic CH; 40.32, CH₂

EXAMPLE 3 Synthesis of 2-(aminoiminomethylamino)methylindane sulfate

Step 1: 2-methylcarboxyindane (D)

A solution of α,α′-dibromo-o-xylene (203.51 g, 0.77 mol) in 1.5 l ofether is added to a solution of diethyl malonate (127 g, 0.79 mol),sodium methoxide (314 ml, 1.70 mol), ethanol (100 ml) and ether (500ml). The mixture is refluxed for 5 hours, then filtered, and finallyconcentrated. The residue is taken up in 500 ml of water. 173 g ofpotassium hydroxide are added, and the mixture is refluxed for 18 hours.The reaction medium is poured into a hydrochloric acid solution and theprecipitate formed is filtered off by suction and then dried. The solidobtained is maintained at 200° C. for 20 minutes and the new solidobtained is recrystallised from 400 ml of heptane. The crystals obtainedare taken up in 400 ml of methanol and, after 5 drops of concentratedsulfuric acid have been added, the mixture is refluxed for 4 hours andthen concentrated. The residue is dissolved in 600 ml of ether. Thisether phase is washed with saturated sodium bicarbonate solution andsaturated sodium chloride solution and then dried over sodium sulfateand concentrated, giving 73.6 g (54%) of a clear oil.

¹H NMR (DMSO-d₆, 200 MHz): δ: 6.96, m, 4H, aromatic H; 3.43, s, 3H, CH₃;3.11, m, 1H, CH; 2.91, m, 4H, CH₂

Step 2 : 2-carboxamide-indane (E)

D (102.1 g, 0.58 mol) and 500 ml of concentrated ammonia solution areintroduced into an autoclave and the mixture is maintained at 80° C. for18 hours. The solid thus formed is filtered off with suction and washedwith water (63.4 g, 68%).

m.p.=181-183° C.

¹H NMR (DMSO-d₆, 200 MHz): δ: 7.39, s, 1H, NH; 7.11, m, 4H, aromatic H;6.85, s, 1H, NH; 3.12-2.97, m, 5H, CH₂ and CH

Step 3: 2-aminomethyl-indane (F)

A solution of E (63 g, 0.391 mol) in tetrahydrofuran (1.5 l) is addeddropwise to a suspension of LiAlH₄ (74.15 g, 1.95 mol) intetrahydrofuran (300 ml) cooled using a cardice/acetone bath, and themixture is then refluxed for 2 hours. The reaction medium is neutralised(75 ml of water, 75 ml of 5M sodium hydroxide and 225 ml of water) andthen filtered. Removal of the solvent leaves an oil (56.9 g, 99%) thatquite readily forms a carbonate.

¹H NMR (DMSO-d₆, 200 MHz): δ: 6.95, m, 4H, aromatic H; 2.90-2.14, m, 7H,3CH₂ and CH; 1.63, s, 2H, NH₂

Step 4: 2-(aminoiminomethylamino)methylindane sulfate

A mixture of F (20.63 g, 0.140 mol), S-methylisothiourea sulfate (19.5g, 0.07 mol) and 10 ml of water is maintained at 90° C. for 30 minutes(end of the evolution of methanethiol gas). The crude solid present isrecrystallised from a water/ethanol mixture to give 12.7 g (38%) of awhite solid.

m.p.=231-233° C.

¹H NMR (DMSO-d₆, 200 MHz): δ: 7.05, m, 4H, aromatic H; 2.95, m, 2H, CH₂;2.40, m, 5H, 2CH₂ and CH

¹³C NMR (DMSO-d6, 50 MHz): δ: 157.07, 142.57, quaternary C; 126.59,124.83, aromatic CH; 45.28, CH₂N; 38.74, CH; 36.57, 2CH₂

EXAMPLE 4 Synthesis of 2-(aminoiminomethylamino)methylbenzothiophenehydrochloride

Step 1: 2-carboxyethylbenzothiophene (G)

Ethyl 2-mercaptoacetate is added to a solution of dimethylformamide (800ml), 2-nitrobenzaldehyde (73 g, 0.48 mol) and potassium carbonate (80 g,0.57 mol) cooled to 0° C., while the temperature is maintained at 0° C.After stirring for 24 hours, the mixture is poured into 2 l of water andthis aqueous phase is extracted with ether. The ether phase is driedover sodium sulfate and concentrated. The crude product obtained ispurified on a column of alumina (petroleum ether) to give 34 g (35%) ofa yellow oil.

¹H NMR (DMSO-d₆, 200 MHz): δ: 8.04, s, 1H, CH; 7.90, m, 2H, aromatic CH;7.35, m, 2H, aromatic H; 4.20, q, 2H, CH₂; 1.93, t, 3H, CH₃

Step 2: 2-carboxamidobenzothiophene (H)

G (34 g, 0.165 mol), concentrated aqueous ammonia (120 ml) and ethanol(50 ml) are maintained at 80° C. in an autoclave for 24 hours. Thesolution is then concentrated and the crude solid is triturated inisopropyl ether and washed with pentane (26 g, 89%).

m.p.=209-211

¹H NMR (DMSO-d₆, 200 MHz): δ: 8.59, s, 1H, NH; 8.32, s, 1H, CH; 8.15, m,2H, aromatic H; 7.89, s, 1H, NH; 7.64, m, 2H, aromatic H

Step 3: 2-aminomethylbenzothiophene (I)

A suspension of H (26 g, 0.146 mol) in tetrahydrofuran (500 ml) is addedto a suspension of LiAlH₄ (33.5 g, 0.88 mol) in tetrahydrofuran (100ml), and the mixture is refluxed for 6 hours. The reaction medium isthen cooled to 0° C. and the excess LiAlH₄ is destroyed (33 ml of H₂O,33 ml of 5 molar sodium hydroxide and 99 ml of H₂O). After filtrationand then concentration, the crude product obtained is purified on acolumn of silica (dichloromethane and then 4/1 dichloromethane/methanol)to give 13 g (56%) of an oil.

¹H NMR (DMSO-d6, 200 MHz): δ: 7.65, m, 2H, aromatic H; 7.12, m, 2H,aromatic H; 7.08, s, 1H, CH; 5.46, m, 2H, NH₂; 4.60, d, 2H, CH₂

Step 4: 2-(aminoiminomethylamino)ethylbenzothiophene hydrochloride

A solution of I (11 g, 0.067 mmol), 1-(aminoiminomethyl)pyrazolehydrochloride (9.8 g, 0.067 mol) and isopropanol (50 ml) is refluxed for24 hours. The reaction medium is concentrated, and the crude solid isrecrystallised from water (7 g, 41%).

m.p.=163-165° C.

¹H NMR (200 MHz): δ: 8.44-7.26, m, 9H, aromatic H and exchangeable H;4.70, d, 2H, CH₂

¹³C NMR (DMSO-d₆, 50 MHz): δ: 157.56, 141.73, 139.49, 139.36, quaternaryC; 124.90, 124.76, 123.88, 122.88, 122.68, aromatic CH; 40.28, CH₂

Table 1 summarises the formulae and characteristics of the compounds ofthe formula (I).

TABLE 1 m.p. in ° C. Compound Structure (Köfler) ¹³C NMR 50 MHz δ ppm 1

203-205(hydrochloride) (DMSO-d₆)168.32, 159.08, 154.12,136.33,quaternary C128.20, 127.27, 124.30and 124.15, aromaticCH53.19, CH₂38.88,NCH₃ 2

171-173(hydrochloride) (DMSO-d₆) 158.56,151.26, 138.98,quaternaryC122.88, 115.76,aromatic CH40.32, CH₂ 3

231-233(sulfate) (DMSO-d₆)157.07, 142.57,quaternary C126.59,124.83,aromatic CH45.28, CH₂N38.74, CH36.57, 2CH₂ 4

163-165(hydrochloride) (DMSO-d₆)157.56, 141.73, 139.49,139.36,quaternary C124.90, 124.76, 123.88,122.88, 122.68,aromatic CH40.28, CH₂5

196-198(hydrochloride) (1H, D2O)8.20-7.50, m, 4H,aromatic H5.00, s, 2H,CH₂ 6

253-255(hydrochloride) (1H, D2O)7.80-7.25, m, 4H,aromatic H4.90, s, 2H,CH₂3.20, s, 3H, NCH₃ 7

Decomposes>130(carbonate) (DMSO-d₆)160.90, 157.71, 136.73,135.58,128.08,quaternary C121.37, 120.16, 119.30,111.59, 100.08,aromaticCH38.51, CH₂ 8

189-191(hemisulfate) (DMSO-d₆)157.68, 151.74, 127.89,quaternary C127.40,124.66, 117.33,108.75, aromatic CH57.99, CHN46.50, CH₂N33.55, CH₂ 9

139-141(carbonate) (DMSO-d₆)159.10, 126.84,quaternary C128.27, 125.57,120.84,109.49, aromatic CH81.04, CHO44.87, CH₂N32.56, CH₂ 10

187-189(carbonate) (DMSO-d₆)160.88, 139.93, 138.91,quaternary C127.83,125.53, 124.72,122.31, aromatic CH48.46, CHS45.54, CH₂N38.97, CH₂ 11

191-193(sulfate) (DMSO-d₆)157.54, 148.11, 134.07,quaternary C108.80,aromatic CH55.89, CH₃O45.77, CH₂N39.22, CH36.76, CH₂ 12

233-235(sulfate) (DMSO-d₆)157.33, 153.86, 136.64,133.10,127.45,quaternary C111.38, 110.51, 102.24,100.20, aromatic CH55.66,CH₃O30.00, CH₂N 13

213-215(sulfate) (DMSO-d₆)162.77, 158.79, 141.39,137.09,133.67,quaternary C117.47, 116.40, 107.18,105.15, aromatic CH60.81,OCH₃43.84, CH₂N 14

181-183(hydrochloride) (DMSO-d₆)157.80, 148.00, 134.80,127.00,quaternary C11.02, 109.50, 104.80,100.30, aromatic CH37.72, CH₂30.28,CH₃ 15

244-247(sulfate) (DMSO-d₆)157.75, 154.49, 128.33,quaternary C124.46,123.23, 121.48,111.35, 104.33,aromatic CH39.92, CH₂ 16

209-211(hydrochloride) (DMSO-d₆)157.31, 144.40, 143.51,quaternaryC128.22, 126.66, 124.80,124.04, 120.96,aromatic CH50.46, 40.33,CH₂36.75, CH3 17

>250(sulfate) (TFA)158.30, 154.00, 149.00,139.00, quaternary C114.5,aromatic CH47.26, 37.12, CH₂40.30, CH

Results of the pharmacological studies will be given hereinbelow.

Study of the Antidiabetic Activity in Nostz Rats

The oral antidiabetic activity of the compounds of the formula (I) wasdetermined on an experimental model of non-insulin-dependent diabetes,induced in the rats with steptozotocin.

The model of non-insulin-dependent diabetes is obtained in the rats bymeans of a neonatal injection (on the day of birth) of steptozotocin.

The diabetic rats used are eight weeks old. The animals are housed, fromthe day of birth to the day of the experiment, in an animal house at aregulated temperature of 21 to 22° C. and subjected to a fixed cycle oflight (from 7 a.m. to 7 p.m.) and darkness (from 7 p.m. to 7 a.m.).Their food consisted of a maintenance diet, and water and food weregiven “ad libitum”, with the exception of fasting two hours before thetests, during which period the food is removed (post-absorptive state).

The rats are treated orally for one (D1) or four (D4) days with the testproduct. Two hours after the final administration of the product and 30minutes after the animals have been anaesthetised with pentobarbitalsodium (Nembutal®), a 300 μl blood sample is taken from the end of thetail.

By way of example, results obtained are collated in Table 2. Theseresults show the efficacy of the compounds of the formula (I) inreducing glycaemia in the diabetic animals. These results are expressedas a percentage change in the glycaemia on D1 and D4 (number of days oftreatment) relative to D0 (before the treatment).

TABLE 2 20 mg/kg/day 200 mg/kg/day Compound D1 D4 D1 D4 1 +5 −4 −9 −23 2−17 −13 −10 −25 3 +2 −10 −14 −29 5 −18 −3 −30 −26 6 +3 0 −6 −16 7 −5 −9−19 −28 8 −7 −12 −10 −9 10  −3 −5 −21 −25 11  −1 −8 −8 −14 12  −22 −2613  −16 −26 15  −23 −28 −29 −31

1. Compounds of the general formula (I)

in which: A represents a benzene or pyridine ring optionally substitutedby one or more of the following groups: branched or unbranched(C₁-C₂₀)alkyl, OR2, where R2 represents: H, branched or unbranched(C₁-C₅)alkyl, (C₃-C₈)cycloalkyl, or benzyl, NR3R4, where R3 and R4represent, independently of each other: H, branched or unbranched(C₁-C₂₀)alkyl, benzyl, acetyl, (C₃-C₈)cycloalkyl, or alternatively R3-R4together form a 3- to 8-membered ring including a nitrogen atom, SR5,where R5 represents: H, branched or unbranched (C₁-C₅)alkyl,(C₃-C₈)cycloalkyl, or benzyl, halogen cyano nitro CO₂R6, where R6represents: H or branched or unbranched (C₁-C₅)alkyl, ortrifluoromethyl, X represents a —CH═, —CH₂—, —NH═ or —NH— radical, Yrepresents a CH₂ radical, an oxygen or sulfur atom or a group —NR7,where R7 represents: H, branched or unbranched (C₁-C₅)alkyl, benzyl,(C₃-C₈)cycloalkyl, or a CH₂CO₂H group, R1 represents one of thefollowing groups H, branched or unbranched (C₁-C₅)alkyl, or benzyl, ortautomeric, enantiomeric, diastereoisomeric or epimeric forms orsolvates or pharmaceutically acceptable salts thereof, with theexception of the compounds of the formula (I) in which: a—A representsan optionally substituted a benzene ring, X represents —CH═ or —CH₂—, Yrepresents an oxygen atom and R1 is a hydrogen atom; b—A represents abenzene ring substituted with a halogen atom or an alkyl or alkoxy grouphaving 1-6 carbon atoms, X represents —CH═, Y represents a sulfur atomand R1 is a hydrogen atom, c—A represents an unsubstituted benzene ring,X represents —CH₂—, R1 is a hydrogen atom or a branched or unbranched(C₁-C₅)alkyl radical and Y represents NR7, where R7 represents ahydrogen atom, a branched or unbranched (C₁-C₅)alkyl radical or a benzylradical, d—A represents an unsubstituted benzene ring, X represents—CH═, R1 is a hydrogen atom and Y represents NR7, where R7 represents anethyl radical, e—A represents a benzene ring, x represents —CH═, R1 is ahydrogen atom and y represents a sulfur atom.
 2. Compounds of theformula (I) according to claim 1, in which the alkyl radicals are C₁-C₅alkyl radicals.
 3. Compounds of the formula (I) according to claim 1, inwhich A represents an optionally substituted benzene ring.
 4. Compoundsof the formula (I) according to claim 1, in which Y represents a —CH₂—radical, a sulfur atom or a group —NR7.
 5. Compounds of the formula (I)according to claim 4, in which Y is a sulfur atom and A represents abenzene ring monosubstituted in a position other than position 5′ of thedouble ring, or a benzene ring substituted by at least two groups. 6.Compounds of the formula (I) according to claim 4, in which Y is a group—NR7 and A represents a substituted beuzene ring.
 7. Compounds of theformula (I) according to claim 1 , in which Y is an oxygen atom, Xrepresents a —CH═ radical or a —CH₂— radical, and A is a substitutedbenzene ring.
 8. Compounds of the formula (I) according to claim 1 , inwhich Y is an oxygen atom and X represents an —N═ or —NH— radical.
 9. Aprocess for preparing a compound according to claim 1, comprising thereaction of a compound of the general formula (II)

in which A, X, Y and R1 are as defined in claim 1, with a guanidylatingagent.
 10. A pharmaceutical composition comprising a compound accordingto claim 1, and a pharmaceutically acceptable carrier.
 11. A method forthe treatment of a pathology associated with insulin resistancesyndrome, comprising administering a compound of formula (I):

in which: A represents a benzene or pyridine ring optionally substitutedby one or more of the following groups: branched or unbranched(C₁-C₂₀)alkyl, OR2, where R2 represents: H, branched or unbranched(C₁-C₅)alkyl, (C₃-C₈)cycloalkyl, or benzyl, NR3R4, where R3 and R4represent, independently of each other: H, branched or unbranched(C₁-C₂₀)alkyl, benzyl, acetyl, (C₃-C₈)cycloalkyl, or alternatively R3and R4 together form a 3- to 8-membered ring including a nitrogen atom,SR5, where R5 represents: H, branched or unbranched (C₁-C₅)alkyl,(C₃-C₈)cycloalkyl, or benzyl, halogen cyano nitro CO₂R6, where R6represents: H or branched or unbranched (C₁-C₅)alkyl, ortrifluoromethyl, X represents a —CH═, —CH₂—, —N═ or —NH— radical, Yrepresents a CH₂ radical, an oxygen or sulfur atom or a group —NR7,where R7 represents: H, branched or unbranched (C₁-C₅)alkyl, benzyl,(C₃-C₈)cycloalkyl, or a CH₂CO₂H group, R1 represents one of thefollowing groups H, branched or unbranched (C₁-C₅)alkyl, or benzyl ortautomeric, enantiomeric, diastereoisomeric or epimeric forms thereof,or solvates or pharmaceutically acceptable salts thereof.
 12. A methodaccording to claim 11, in which the pathology is diabetes.
 13. A methodaccording to claim 11, in which the pathology is dyslipidaemia.
 14. Amethod according to claim 11, in which the pathology is obesity.
 15. Amethod according to claim 14, in which the pathology is atherosclerosis,retinopathies or neuropathies.
 16. Compounds of the general formula (I)

in which: A represents a benzene or pyridine ring optionally substitutedby one or more of the following groups: OR2, where R2 represents: H,(C₃-C₈)cycloalkyl, or benzyl, NR3R4, where R3 and R4 represent,independently of each other: H, branched or unbranched (C₁-C₂₀)alkyl,benzyl, acetyl, (C₃-C₈)cycloalkyl, or alternatively R3 and R4 togetherform a 3- to 8-membered ring including a nitrogen atom, SR5, where R5represents: H, branched or unbranched (C₁-C₅)alkyl, (C₃-C₈)cycloalkyl,or benzyl, cyano nitro CO₂R6, where R6 represents: H or branched orunbranched (C₁-C₅)alkyl, or trifluoromethyl, X represents a —CH═, —CH₂—,—N═ or —NH— radical, Y represents a CH₂ radical, an oxygen or sulfuratom or a group —NR7, where R7 represents: H, branched or unbranched(C₁-C₅)alkyl, benzyl, (C₃-C₈)cycloalkyl, or a CH₂CO₂H group, R1represents one of the following groups H, branched or unbranched(C₁-C₅)alkyl, or benzyl, or tautomeric, enantiomeric, diastereoisomericor epimeric forms or solvates or pharmaceutically acceptable saltsthereof, with the exception of the compounds of the formula (I) inwhich: a - A represents an optionally substituted benzene ring, Xrepresents —CH═or —CH₂—, Y represents an oxygen atom and R1 is ahydrogen atom; c - A represents an unsubstituted benzene ring, Xrepresents —CH₂—, R1 is a hydrogen atom or a branched or unbranched(C₁-C₅)alkyl radical and Y represents NR7, where R7 represents ahydrogen atom, a branched or unbranched (C₁-C₅)alkyl radical or a benzylradical, d - A represents an unsubstituted benzene ring, X represents—CH═, R1 is a hydrogen atom and Y represents NR7, where R7 represents anethyl radical, e - A represents a benzene ring, x represents —CH═, R1 isa hydrogen atom and y represents a sulfur atom.
 17. Compounds of thegeneral formula (I)

in which: A represents a benzene or pyridine ring optionally substitutedby one or more of the following groups: branched or unbranched(C₁-C₂₀)alkyl, OR2, where R2 represents: H, branched or unbranched(C₁-C₂₀)alkyl, (C₃-C₈)cycloalkyl, or benzyl, NR3R4, where R3 and R4represent, independently of each other: H, branched or unbranched(C₁-C₂₀)alkyl, benzyl, acetyl, (C₃-C₈)cycloalkyl, or alternatively R3and R4 together form a 3- to 8-membered ring including a nitrogen atom,SR5, where R5 represents: H, branched or unbranched (C₁-C₅)alkyl,(C₃-C₈)cycloalkyl, or benzyl, cyano nitro CO₂R6, where R6 represents: Hor branched or unbranched (C₁-C₅)alkyl, or trifluoromethyl, X representsa —CH═, —CH₂—, —N═ or —NH— radical, Y represents a CH₂ radical, anoxygen or sulfur atom or a group —NR7, where R7 represents: H, branchedor unbranched (C₁-C₅)alkyl, benzyl, (C₃-C₈)cycloalkyl, or a CH₂CO₂Hgroup, R1 represents one of the following groups H, branched orunbranched (C₁-C₅)alkyl, or benzyl, or tautomeric, enantiomeric,diastereoisomeric or epimeric forms or solvates or pharmaceuticallyacceptable salts thereof, with the exception of the compounds of theformula (I) in which: a - A represents an optionally substituted benzenering, X represents —CH═or —CH₂—, Y represents an oxygen atom and R1 is ahydrogen atom; b- A represents a benzene ring, optionally substitutedwith halogen or an alkyl or alkoxy group having 1-6 carbon atoms, X is—CH═, Y is S and R1 is hydrogen, c - A represents an unsubstitutedbenzene ring, X represents —CH₂—, R1 is a hydrogen atom or a branched orunbranched (C₁-C₅)alkyl radical and Y represents NR7, where R7represents a hydrogen atom, a branched or unbranched (C₁-C₅)alkylradical or a benzyl radical, d - A represents an unsubstituted benzenering, X represents —CH═, R1 is a hydrogen atom and Y represents NR7,where R7 represents an ethyl radical, e - A represents a benzene ring, xrepresents —CH═, R1 is a hydrogen atom and y represents a sulfur atom.